Aspirin (acetylsalicylic acid, ASA) has been available for use as an analgesic-antipyretic for almost a century and novel therapeutic applications for this drug, for example in lowering the risk of myocardial infarction or as a prophylaxis against colorectal cancer, continue to be uncovered (Weissmann, G. (1991) Sci. Am. 264, 84-90; Ridker, P. M., Cushman, M., Stampfer, M. J., Tracy, R. P. and Hennekens, C. H. (1997) N. Engl. J. Med. 336, 973-979; Marcus, A. J. (1995) N. Engl. J. Med. 333, 656-658). The acetylation of cyclooxygenases I and II (COX I and II) and the subsequent irreversible inhibition of prostaglandin (PG) and thromboxane biosyntheses are well understood mechanisms of some of ASA""s pharmacological actions (Marcus, A. J. (1995) N. Engl. J. Med. 333, 656-658; Herschman, H. R. (1998) Trends Cardiovasc. Med. 8, 145-150). More recently, ASA was found to cause a switch in eicosanoid biosynthesis as the acetylation of COX II changes the enzyme""s activity to produce 15R-hydroxyeicosatetraenoic acid from agonist-released arachidonic acid Herschman, H. R. (1998) Trends Cardiovasc. Med. 8, 145-150). Human neutrophils, and other cells possessing 5-lipoxygenase, utilize this substrate via transcellular biosynthetic routes to produce 15-epi-lipoxin A4 (15-epi-LXA4) and 15-epi-lipoxin B4 (15-epi-LXB4) (Serhan, C. N. (1997) Prostaglandins 53, 107-137; Chiang, N., Takano, T., Clish, C. B., Petasis, N. A., Tai, H. -H. and Serhan, C. N. (1998) J. Pharmacol. Exp. Ther. 287, 779-790). These aspirin-triggered lipoxins (ATL) arc the endogenous 15R enantiomeric counterparts of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), respectively, and share their bioactivities (Serhan, C. N. (1997) Prostaglandins 53, 107-137(5)).
Unlike other eicosanoids (e.g., leukotrienes, PGs, etc.), which are generally considered local pro-inflammatory mediators, lipoxins (LX) display potent inhibitory actions in several key events in inflammation, such as polymorphonuclear cell (PMN) chemotaxis, transmigration across endothelial and epithelial cells, and diapedesis from post-capillary venules (Serhan, C. N. (1997) Prostaglandins 53, 107-137(5)). LX are generated in several pathogenic scenarios in vivo, for example: in lung tissue of patients with severe pulmonary disease; and by PMN from patients with asthma or rheumatoid arthritis, where their presence is proposed to be linked to long-term clinical improvement (Lee, T. H., Crea, A. E., Gant, V., Spur, B. W., Marron, B. E., Nicolaou, K. C., Reardon, E., Brezinski, M. and Serhan, C. N. (1990) Am. Rev. Respir. Dis. 141, 1453-1458; Chavis, C., Chanez, P., Vachier, I., Bousquet, J., Michel, F. B. and Godard, P. (1995) Biochem. Biophys. Res. Commun. 207, 273-279; Chavis, C., Vachier, I., Chanez, P., Bousquet, J. and Godard, P. (1996) J. Exp. Med. 183, 1633-1643; Thomas, E., Leroux, J. L., Blotman, F. and Chavis, C. (1995) Inflamm. Res. 44, 121-124). Interestingly, ATL show an even greater level of inhibition than native LX in preventing neutrophil adhesion, where they are xcx9ctwice as potent (Serhan, C. N. (1997) Prostaglandins 53, 107-137). ATL are also more potent inhibitors of microbial induction of cytokine release. Specifically, 15-epi-LXA4 showed greater inhibition than LXA4 of S. typhimurium-induced secretion and gene regulation of the potent leukocyte chemoattractant IL-8, generated by intestinal epithelial cells (Gewirtz, A. T., McCormick, B., Neish, A. S., Petasis, N. A., Gronert, K., Serhan, C. N. and Madara, J. L. (1998) J. Clin. Invest. 101, 1860-1869). It is therefore likely that, in addition to the inhibition of prostaglandin formation, the benefits of ASA therapy also result from the triggering of novel anti-inflammatory lipid mediators that act locally to down regulate leukocytes.
In one aspect, the present invention is directed to compounds having the formulae (I-V): 
wherein X is R1, OR1, or SR1;
wherein R1 is
(i) a hydrogen atom;
(ii) an alkyl of 1 to 8 carbons atoms, inclusive, which may be straight chain or branched;
(iii) a cycloalkyl of 3 to 10 carbon atoms;
(iv) an aralkyl of 7 to 12 carbon atoms;
(v) phenyl;
(vi) substituted phenyl 
wherein Zi, Zii, Ziii, Ziv and Zv are each independently selected from xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R1, xe2x80x94SO3H, a hydrogen atom, halogen, methyl, xe2x80x94ORx, wherein Rx is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl;
(vii) a detectable label molecule; or
(viii) a straight or branched chain alkenyl of 2 to 8 carbon atoms, inclusive;
wherein Q1 is (Cxe2x95x90O), SO2 or (CN), provided when Q1 is CN, then X is absent;
wherein Q3 and Q4 are each independently O, S or NH;
wherein one of R2 and R3 is a hydrogen atom and the other is
(a) H;
(b) an alkyl of 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched;
(c) a cycloalkyl of 3 to 6 carbon atoms, inclusive;
(d) an alkenyl of 2 to 8 carbon atoms, inclusive, which may be straight chain or branched; or
(e) RaQ2Rb wherein Q2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; wherein Ra is alkylene of 0 to 6 carbons atoms, inclusive, which may be straight chain or branched and wherein Rb is alkyl of 0 to 8 carbon atoms, inclusive, which may be straight chain or branched, provided when Rb is 0, then Rb is a hydrogen atom;
wherein R4 is
(a) H;
(b) an alkyl of 1 to 6 carbon atoms, inclusive, which may be a straight chain or branched;
wherein R5 is 
wherein Zi, Zii, Ziii, Ziv and Zv are each independently selected from xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R1, xe2x80x94SO3H, a hydrogen atom, halogen, methyl, xe2x80x94ORx, wherein Rx is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl or a substituted or unsubstituted, branched or unbranched alkyl group;
wherein Y1 is xe2x80x94OH, methyl, xe2x80x94SH, an alkyl of 2 to 4 carbon atoms, inclusive, straight chain or branched, an alkoxy of 1 to 4 carbon atoms, inclusive, or CHaZb where a+b=3, a=0 to 3, b=0 to 3 and Z is cyano, nitro or a halogen;
wherein R6 is
(a) H;
(b) an alkyl from 1 to 4 carbon atoms, inclusive, straight chain or branched;
wherein T is O or S, and pharmaceutically acceptable salts thereof excluding 16-phenoxy-LXA4 and/or 15-epi-16-(para-fluoro)-phenoxy-LXA4 in certain embodiments.
In preferred embodiments, X is OR1 wherein R1 is a hydrogen atom, an alkyl group of 1 to 4 carbon atoms or a pharmaceutically acceptable salt, Q1 is Cxe2x95x90O, R2 and R3, if present, are hydrogen atoms, R4 is a hydrogen atom or methyl, Q3 and Q4, if present, are both O, R6, if present, is a hydrogen atom, Y1, if present, is OH, T is O and R5 is a substituted phenyl, e.g., 
wherein Zi, Zii, Ziii, Ziv and Zv are each independently selected from xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R1, xe2x80x94SO3H, a hydrogen atom, halogen, methyl, xe2x80x94ORx, wherein Rx is 1 to 8 carbon atoms, inclusive, which may be a straight chain or branched, and hydroxyl. In certain embodiments for R5, 15-epi-16-para-fluorophenyl, 15-epi-unsubstituted phenyl, 16-parafluorophenyl or 16-phenyoxy are excluded.
In another aspect, the present invention is directed to an in vivo method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation. The method includes administering to a subject an effective anti-inflammatory amount of a pharmaceutical composition including a compound having one of the above-described formulae.
In another aspect, the invention is directed to a method for modulating a disease or condition associated with polymorphoneutrophil (PMN) inflammation. The method includes administering to a subject an effective anti-inflammatory amount of a pharmaceutical composition including a compound having one of the above-described formulae.
In still another aspect, the present invention is directed to pharmaceutical compositions including compounds having the above-described formulae and a pharmaceutically acceptable carrier. In one embodiment, a preferred compound is 
In a preferred embodiment, the pharmaceutical carrier is not a ketone, e.g., acetone.
In yet another aspect, the present invention is directed to a packaged pharmaceutical composition for treating a PMN responsive state in a subject. The packaged pharmaceutical composition includes a container holding a therapeutically effective amount of at least one lipoxin compound having one of the formulae described above and instructions for using the lipoxin compound for treating an PMN responsive state in the subject.